Saliva is a natural fluid whose function is essential for oropharyngeal, digestive and general health. Salivary function is apparently simple; however, the complexity of its composition reflects its large number of properties. When the amount or quality of saliva diminishes, multiple problems occur called xerostomia or “dry mouth” or “burning mouth”.
The WDF (World Dental Federation) defines it as the “modern man's disease” due to its high incidence. The percentages it has established range from 20% in people around 20 years of age, and 40% in people of 60 years of age, being higher in older age groups.
Xerostomia or dry mouth is a universal problem that can affect anybody, independently of their sex, race, age or other conditions. However, it is more frequent in women than in men, mainly due to the reduction of oestrogen hormones in perimenopause, in the same manner as dryness appears in other mucosa such as the vagina and the eyes. One of every four adults suffers from dry mouth. Furthermore, it is associated to multiple systemic and psychiatric diseases, and more importantly, it appears as a secondary effect to multiple treatments of these and other diseases that are becoming more frequent, even reaching epidemic characteristics. Among these are diabetes, cancer, anxiety, depression, allergies, autoimmune diseases, stress or alcoholism, for example.
It is for all the former that xerostomia or “dry mouth syndrome” is so relevant today. Furthermore, it is a syndrome that can be silent in many cases and that may not show symptoms until it is very advanced. 50% of xerostomia patients do not show any symptoms, and what is scientifically more relevant, up to 50% of salivary flow may be lost without yet perceiving dryness in the mouth or before xerostomia manifests itself with signs or symptoms.
Xerostomia or dry mouth syndrome affects both people with dentition (toothed patients) and toothless patients. The consequences of said xerostomia in the first group are very manifest, since an alteration of the natural buffering capacity of saliva also occurs a few months after syndrome instauration, due to the deficit in salivary flow, leading to short-term structural deterioration of the hard tissues in the mouth (teeth).
In toothed patients with xerostomia, the saliva that under normal physiological conditions acts as a defence, barrier and reinforcement, is no longer effective or sufficient to slow down the demineralization of enamel and dentin caused by daily aggressions (cariogenic bacteria, acids, drops in pH, dental bruxism or clenching . . . ) Thus, for example, rapidly evolving caries and atypical caries such as neck caries occur as a result of the postprandial (after eating) decrease in oral pH, which can completely destroy teeth in a few months. Furthermore, a whole series of symptoms and signs can occur, independently of whether there are teeth or not, which can even alter the patient's quality of life.
In toothless patients, xerostomia does not cause dental destruction since the patient has already lost all his teeth. However, the appearance of signs and symptoms can be even greater than for the first group.
Different types of glands are responsible for said secretions: mucilaginous saliva is secreted by the minor salivary glands (labial, palatine, lingual), whereas aqueous saliva is secreted by the parotid and submaxillary glands in much larger amounts.
Dry mouth symptoms are frequently present in patients whose salivary secretion, both stimulated and unstimulated, is normal. In contrast, there are patients with true hyposalivation who do not complain of buccal dryness. Perception by the patient largely depends on the salivary component that is lacking: buccal dryness is felt when mucilaginous components are missing (scientifically called resting or unstimulated saliva) which lubricate and provide comfort, although the amount of salivary flow (flow of aqueous or stimulated saliva) may be the same. In contrast, patients with a decrease in salivary flow may not perceive dryness if they preserve mucilaginous saliva.
Today it is known that it is resting or unstimulated saliva which prevents the symptoms and protects both soft tissues (tongue and mucosa) and hard tissues (teeth). A comparison could be made with tears (crying) when upset, which do not perform the function of protecting the eye, since they fall down the face, very different to lachrymal secretion that lubricates and protects ocular structures from the external medium, protecting normal vision.
Both kinds of saliva, stimulated and unstimulated or resting, are notably different in volume, glandular origin and composition. Resting saliva is that which lubricates and provides the feeling of calmness. One of the preferred theories indicates that this may be due to the high concentration of potassium ions in their buffer system, which, scientifically, is the most used cation in desensitizing toothpastes and gels. In contrast, stimulated saliva has large amounts of sodium.
There is great individual variability regarding salivary flow. It can differ by up to 50%.
Xerostomia makes talking, chewing and swallowing difficult, and also oral hygiene since it favours the accumulation of dental plaque because the salivary flow no longer washes out bacteria. Furthermore, it reduces the buffer effect of saliva, making the pH become acid and destroying the teeth. It is related to many chronic pharyngitis, mucositis and even to digestive disorders. At a local level it can cause a feeling of burning and/or pain in the soft tissues and in the tongue, a need for moisturizing the mouth at short time intervals, leaves surfaces of the teeth rough, a sliver of saliva between the teeth or the tongue and the palate, a feeling of pressure or tightness in a group of teeth and even pain. It causes a fast progression of tooth decay, it facilitates periodontal diseases (gingivitis), and it wears out teeth due to greater abrasion and friction without lubrication between dental surfaces. It also causes fissures in the lips and bacterial infections (candidiasis, sialodentitis), halitosis, and it can even produce eating disorders, insomnia, irritability or depression. Likewise, xerostomia affects the sufferer's quality of life from the point of view of sociability: there is a lack of interest for eating in company, for going out or for talking in groups.
The ethiology of xerostomia involves many factors and is highly complex:
1. Consumption of mouth-drying drugs: More than 500 families of drugs have xerostomia as a side effect, this being one of the main reasons for medication discontinuation by patients. These are responsible for most cases of xerostomia. Salivary deficiency usually lasts a long time after an extended treatment, despite drug discontinuation.
The drugs that produce this effect most frequently are diuretics (hydrochlorothiazide, amiloride), sedatives, antidepressants (serotonin reuptake inhibitors and especially tricyclic antidepressants), antihypertensives, antiinflammatory drugs, decongestants (phenylpropanolamine, pseudoephedrine), anxiolytic drugs (diazepam), anticholinergic-type antispasm drugs (atropine, oxybutynin), antidiarrheal (loperamide, diphenoxylate), antihistamines (chlorphenamine, loratadine), non-steroid antiinflammatory drugs (piroxicam, ibuprofen), opioid analgesics (morphine), muscle relaxants (baclofen), bronchodilators (ipratropium, salbutamol), antiparkinson drugs (levodopa, biperiden), antiacne drugs (isotretinoin) and antipsychotics such as phenothiazines and butyrophenones.
2. Oncological treatments such as head and neck radiotherapy (one of the most widely recognised causes). Also, and more frequently, oncological chemotherapy. And also radioactive iodine therapy in thyroid carcinoma.
3. Autoimmune diseases: they permanently reduce salivary flow. We can highlight Sjögren's Syndrome, systemic lupus erythematosus, rheumatoid arthritis, polymyositis/dermatomyositis and scleroderma.
4. Infectious diseases: HIV, hepatitis.
5. Transplant patients with immunosuppressive therapy: salivary gland hypofunction.
6. Dialysis patients.
7. Systemic diseases such as diabetes, arthritis, Alzheimer and senile dementia.
8. Psychiatric diseases such as anxiety, depression and nervous anorexia.
9. Consumption of addictive substances such as alcohol, tobacco and drugs. A common factor in our times.
In any case, it is important to diagnose and treat xerostomia because as well as the loss of quality of life for the patient, it also seriously affects the patient's health.
This shows that xerostomia is a very complex syndrome. Until now there have only been failed attempts regarding treatment, focused on imitating natural saliva with artificial products that try to substitute the absent natural saliva.
Thus, until now attempts had been made in the sense of creating artificial salivas, although said products are not exempt of critiques, since in general, due to their rheologic and organoleptic features, they are usually gels with acid, even very acid, pH levels, with the subsequent risk this entails for the dry mouth patient. (“Dental Management and Treatment of Xerostomic Patients”, by Dr. Carl W. Haveman, D.D.S., M.S., Director, Advanced General Dentistry Clinic, The University of Texas Health Science Center at San Antonio—Texas Dental Journal, June 1998, pp. 43 to 56); “The effect of commercially available saliva substitutes on predemineralised bovine dentin in vitro”, by Department of Operative Dentistry and Periodontology. University School of Dental Medicine, Freie Unversitaet, Berlin, Germany—Oral Diseases #8, pp. 192-198).
Therefore, there is still a need in the state of the art for providing alternative compositions for treating xerostomia that increase the flow of resting or unstimulated saliva.
The present inventors have discovered that the combination of olive oil, trimethylglycine and xylitol has a synergic effect since it surprisingly achieves increasing in almost 200% the salivary flow of resting or unstimulated saliva, managing to alleviate the symptoms of dry mouth syndrome, including pain, and improving the quality of life of patients.
A study by Kelly et al. (“Bioadhesive, Theological, lubricant and other aspects of an oral gel formulation intended for the treatment of Xerostomia”, H. M. Kelly, P. B. Deasy, M. Busquet, A. A. Torrance. School of Pharmacy, Trinity College, University of Dublin, Ireland—International Journal of Pharmaceutics 2004 #278, pp. 391-406), describes an artificial saliva with sialogogues or stimulants based on potassium chloride, sodium chloride, calcium chloride and magnesium chloride, which are also those which increase the flow of stimulated saliva and which can also comprise sunflower oil or olive oil in order to improve the bioadhesion and viscosity thereof, although the authors indicate the curiosity that the saliva is neither sticky or viscous. The use of olive oil has also been described as a greasy vehicle in compositions for treating dermatological disorders related to dry mucosa (patents US 200528174 and AT 414095).
Xylitol has been included as an ingredient in numerous products for dry mouth, with a proven benefit as a non-carcinogenic sweetening agent (see, for example, patent ES 2186569). However, it has not been possible to prove its capacity per se for stimulating salivary flow (Caries Res. 1993; 27(1) :55-9; Caries Res. 1999; 33(1) :23-31). In fact, its function as a salivary stimulant in chewing gum and confectionery products, described in patent ES 2057412, for example, seems to be due more to the vehicle, since any gum, hard or soft plastic in the mouth is capable of promoting stimulated salivary flow even without any active ingredients (J. Dent. Res. 1989; 68(5):786-90).
On the other hand, U.S. Pat. No. 5,156,845 describes the use of betaine hydrochloride to stimulate stimulated salivary flow based on the acidity the molecule contributes to the composition. Likewise, U.S. Pat. No. 6,156,293 by Jutila, defines the use of trimethylglycine to alleviate the symptoms of dry mucosa and membranes of the body in non-therapeutic preparations, since they do not increase any vital physiological function. The author describes trimethylglycine as a bipolar compound that can adhere to the surface of mucosal membranes and stay there for some time binding water and thus moistening them.
However, the combined use of olive oil, xylitol and trimethylglycine has not been described in the state of the art as a therapeutic composition for improving salivary physiological function in treating xerostomia. The composition of the invention does not only achieve alleviating the most important symptoms of this serious problem, but also, thanks to the surprising increase in unstimulated salivary flow, it achieves all the benefits provided by natural saliva.
Furthermore, also surprisingly, said synergic combination is capable of protecting against dentin demineralization, whereas none of the ingredients separately achieves this, thus preventing or reducing problems related to xerostomia such as caries, for example.
Buchalla et al. (“Influence of Olive Oil Emulsions on Dentin Demineralization in vitro”, W. Buchalla, T. Attin, P. Roth, E. Hellwig. Freiburg University, Germany—Caries Research 2003 #37, pp. 100 to 107), have described the protective effect against dentin demineralisation of oily emulsions with 5% and 50% of olive oil, concluding that the latter protects more than the first, but without significant differences. Likewise, the studies by Featherstone and Rosenberg (Caries Res 18 (1984) 52-55) had shown that lipids provide a diffusion film in the organic aquo-lipo-proteic matrix of enamel, hindering the occurrence of caries.
On the other hand, the results obtained from the erosion protection studies enclosed do not reveal any capacities of olive oil for protecting against demineralisation under the conditions in which the combination of the three ingredients do so in enamel and dentin.
Furthermore, the combination of the three components of the composition of the invention has not been suggested or described to have such a surprising effect regarding preventing the loss of dentin, greater than that provided by the ingredients independently. This property is especially important in xerostomia patients, since gum dehydration produces an exposure of dentin, which is especially sensitive to demineralisation.
Therefore, the composition of the present invention combining the active ingredients mentioned allows treatment of xerostomia or disorders associated with it with very good results in increasing the flow of resting saliva, in alleviating the symptoms and pain associated to xerostomia as well as improving the quality of life of affected persons. Furthermore, the composition of the invention has been proved to protect against demineralisation of dentin subjected to extreme pH conditions similar to those existing in the mouth without saliva.